Scenario 2 Drug screening 1 oclock position in Figure

Once the target protein is identified, the search for the drug starts. That search is again composed of a mixture of experimental and computer-based procedures. In a first phase, one is looking for a lead compound. The only requirement on the lead compound is that it binds tightly to the binding site of the target protein. In a second step of lead optimization, the lead compound is modified to be non-toxic, have few side effects and be bioaccessible, i.e. be easily delivered to the site in the body, at which its effect is desired.

Basically, there are two approaches to developing a new drug. One is to create one from scratch. This has been attempted on the basis of the knowledge of the three-dimensional structure of the binding site of the protein. In effect, the drug molecule can be designed to be complementary to the binding site in steric and physicochemical terms. This approach is called ab initio drug design (not to be confused with ab initio protein structure prediction or ab initio methods in theoretical chemistry). Ab initio drug design has been hampered by the fact that often the developed molecules were hard to synthesize. Furthermore lead optimization turned out to be hard for many lead compounds developed with ab initio design techniques.

The second approach is to screen through a large database of known molecules and check their binding affinity to the target protein. The advantage of this approach is that, mostly, the compounds that have been accumulated in a database have been investigated before - though mostly in a different context. Their bioaccessibility and toxicity may have been studied and they probably have been synthesized. Screening compounds from a library can been done in the laboratory or in the computer. In the latter case, the process is called virtual screening. Compound databases become large, so a mixture of the two processes may be advisable. Here, a set of compounds is preselected from a large library with virtual screening. These compounds are then tested in the laboratory. Chapter 6 of volume 2 by Matthias Rarey, Martin Stahl, and Gerhard Klebe gives more detail on virtual drug screening.